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GW4064作为法尼醇X受体激动剂的新型杂环支架

Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists.

作者信息

Smalley Terrence L, Boggs Sharon, Caravella Justin A, Chen Lihong, Creech Katrina L, Deaton David N, Kaldor Istvan, Parks Derek J

机构信息

Muscle Metabolism DPU, Metabolic Pathways & Cardiovascular Discovery Performance Unit, GlaxoSmithKline, Inc., Five Moore Drive, Research Triangle Park, NC 27709, United States.

Muscle Metabolism DPU, Metabolic Pathways & Cardiovascular Discovery Performance Unit, GlaxoSmithKline, Inc., Five Moore Drive, Research Triangle Park, NC 27709, United States.

出版信息

Bioorg Med Chem Lett. 2015 Jan 15;25(2):280-4. doi: 10.1016/j.bmcl.2014.11.050. Epub 2014 Nov 26.

DOI:10.1016/j.bmcl.2014.11.050
PMID:25499883
Abstract

The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs.

摘要

法尼醇X受体(FXR)可能在多种代谢性疾病中发挥关键作用,因此,它有可能成为开发治疗这些疾病的疗法的靶点。先前的研究将GW4064描述为一种具有有趣活性特征的FXR激动剂。本手稿将描述GW4064新型类似物的合成及其类似物的活性特征。

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1
Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists.GW4064作为法尼醇X受体激动剂的新型杂环支架
Bioorg Med Chem Lett. 2015 Jan 15;25(2):280-4. doi: 10.1016/j.bmcl.2014.11.050. Epub 2014 Nov 26.
2
Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064.法尼醇X受体(FXR)激动剂GW4064的取代异恶唑类似物。
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Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties.GW4064的片段化产生了一种具有高效能的部分法尼醇X受体激动剂,其类药性质得到了改善。
Bioorg Med Chem. 2015 Jul 1;23(13):3490-8. doi: 10.1016/j.bmc.2015.04.035. Epub 2015 Apr 18.
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A formulation-enabled preclinical efficacy assessment of a farnesoid X receptor agonist, GW4064, in hamsters and cynomolgus monkeys.法尼醇 X 受体激动剂 GW4064 在仓鼠和食蟹猴中的配方支持的临床前疗效评估。
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Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: Understanding and improving key determinants of pharmacological properties.具有环丙基、羟基环丁基和羟基氮杂环丁烷基连接基的新型取代异恶唑法尼醇X受体激动剂:理解和改善药理性质的关键决定因素
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Synthesis of Novel Farnesoid X Receptor Agonists and Validation of Their Efficacy in Activating Differentiation of Mouse Bone Marrow-Derived Mesenchymal Stem Cells into Osteoblasts.新型法尼醇 X 受体激动剂的合成及其在激活小鼠骨髓间充质干细胞向成骨细胞分化中的功效验证。
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Knocking on FXR's door: the "hammerhead"-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities.叩响法尼醇X受体(FXR)之门:FXR激动剂的“锤头状”结构系列——具有强大体外和体内活性的两亲性异恶唑类化合物
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Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery.基于时间分辨荧光共振能量转移的法尼醇 X 受体拮抗剂发现的分析方法的建立。
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Unbinding pathways of GW4064 from human farnesoid X receptor as revealed by molecular dynamics simulations.通过分子动力学模拟揭示 GW4064 与人法尼醇 X 受体的解结合途径。
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Farnesoid X receptor agonist GW4064 indirectly inhibits HCV entry into cells via down-regulating scavenger receptor class B type I.法尼醇 X 受体激动剂 GW4064 通过下调清道夫受体 B 类 I 型间接抑制 HCV 进入细胞。
Eur J Pharmacol. 2019 Jun 15;853:111-120. doi: 10.1016/j.ejphar.2019.03.033. Epub 2019 Mar 19.

引用本文的文献

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Geniposidic Acid Targeting FXR "S332 and H447" Mediated Conformational Change to Upregulate CYPs and miR-19a-3p to Ameliorate Drug-Induced Liver Injury.京尼平苷酸靶向FXR“S332和H447”介导的构象变化以上调细胞色素P450酶和miR-19a-3p以改善药物性肝损伤。
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Synthesis of Novel Farnesoid X Receptor Agonists and Validation of Their Efficacy in Activating Differentiation of Mouse Bone Marrow-Derived Mesenchymal Stem Cells into Osteoblasts.
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